The H5N1 avian influenza epidemic that has ravaged multiple species in Asia, now threatens the United States. National response plans call for aggressive human case identification, antiviral use, isolation, and possibly quarantine. The mathematical models upon which the pandemic plans rely lack fundamental objective data such as transmission rates and virus infectiousness. As human disease detection in Asia is based upon clinical encounters, little is known regarding subclinical infections or risk factors for H5N1 infection. Our long term goa/in this proposed research is to epidemiologically describe clinical and subclinical H5N1 transmission such that public health officials might design appropriate H5N1 surveillance and control measures. In this effort we will conduct a controlled, three-year, prospective study of H5N1 transmission among 900 adults occupationally exposed to poultry (poultry farmers, poultry industry workers, meat processing workers, open poultry market workers), and 300 age-group and gender matched non-exposed controls living in three H5N1 endemic areas in Asia: Tangerang, Indonesia;Bali, Indonesia;and Kandaal Province, Cambodia. The study will involve aggressive active surveillance for influenza-like illness among study participants (with nasopharyngeal swab and serum sampling), annual serial serological follow-up of participants, and through home visits, similar studies of the family members exposed to study subjects who develops influenza infection. Microneutralization serologic techniques, RT-PCR, and viral culture will be used to determine influenza infection outcomes. Our objectives are to determine the seroprevalence of evidence of previous H5N1 influenza infection, to estimate the annual incidence of H5N1 influenza infection, to estimate secondary H5N1 influenza infection rates, and to determine risk factors for H5N1 influenza infection. Based upon preliminary data, our central hypotheses are that H5N1 influenza infection will be frequent among these workers, that we will be able to estimate the prevalence and incidence of H5N1 infection, and that we will be able to identify persons at highest risk of H5N1 infection. We are particularly well-suited to conduct this work as we have extensive experience conducting both epidemiological and laboratory-based studies of influenza transmission, and we have exceptional cooperation among public health officials nationally and locally at the field sites. This study is innovative in that no such prospective studies of avian influenza infection have been performed among those person's occupationally exposed to poultry in H5N1 endemic sites.